Calcium‐activated potassium channels and endothelial dysfunction: therapeutic options?

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Abstract
The three subtypes of calcium‐activated potassium channels (KCa) of large, intermediate and small conductance (BKCa, IKCaand SKCa) are present in the vascular wall. In healthy arteries, BKCachannels are preferentially expressed in vascular smooth muscle cells, while IKCaand SKCaare preferentially located in endothelial cells. The activation of endothelial IKCaand SKCacontributes to nitric oxide (NO) generation and is required to elicit endothelium‐dependent hyperpolarizations. In the latter responses, the hyperpolarization of the smooth muscle cells is evoked either via electrical coupling through myo‐endothelial gap junctions or by potassium ions, which by accumulating in the intercellular space activate the inwardly rectifying potassium channel Kir2.1 and/or the Na+/K+‐ATPase. Additionally, endothelium‐derived factors such as cytochrome P450‐derived epoxyeicosatrienoic acids and under some circumstances NO, prostacyclin, lipoxygenase products and hydrogen peroxide (H2O2) hyperpolarize and relax the underlying smooth muscle cells by activating BKCa. In contrast, cytochrome P450‐derived 20‐hydroxyeicosatetraenoic acid and various endothelium‐derived contracting factors inhibit BKCa. Aging and cardiovascular diseases are associated with endothelial dysfunctions that can involve a decrease in NO bioavailability, alterations of EDHF‐mediated responses and/or enhanced production of endothelium‐derived contracting factors. Because potassium channels are involved in these endothelium‐dependent responses, activation of endothelial and/or smooth muscle KCacould prevent the occurrence of endothelial dysfunction. Therefore, direct activators of these potassium channels or compounds that regulate their activity or their expression may be of some therapeutic interest. Conversely, blockers of IKCamay prevent restenosis and that of BKCachannels sepsis‐dependent hypotension.Mandarin translation of

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